With Atlas Cash and Berkeley Tools, Intellia Joins the CRISPR Fray

Add another entrant to the race toward what might be called Gene Therapy 2.0.

Atlas Venture and the research arm of the drug giant Novartis (NYSE: NVS) have put $15 million into the Series A round for Intellia Therapeutics, which is emerging today from stealth after two years of incubation.

The Cambridge, MA, startup will use a new gene editing technology, known in shorthand as CRISPR/Cas9, to develop human therapeutics. It has exclusive license to a suite of tools and intellectual property developed by a Berkeley, CA, startup called Caribou Biosciences, which has close ties to a scientist, Jennifer Doudna, who might one day win a Nobel Prize for her CRISPR/Cas9 work.

Similar to the adoption of RNA interference more than a decade ago, CRISPR/Cas9 has taken the biomedical research world by storm for its ease of use in modifying the genomes of a range of organisms and animals. (The first monkeys with CRISPR-edited genomes were born earlier this year.)

But will it work on humans? Intellia is joining Editas Medicine, also of Cambridge, and London, UK-based CRISPR Therapeutics as the first startups to try to find out—or at least to say so publicly. Atlas seeded and incubated the firm, or the idea for it, for two years. But only in the past few months did the shape of it—and the incorporation of Caribou’s technology platform—come together.

Intellia’s CEO is Nessan Bermingham (pictured), also a venture partner at Atlas. Other executives include chief scientific officer Thomas Barnes, formerly of Eleven Biotherapeutics (NASDAQ: EBIO); chief medical officer John Leonard, the former chief scientific officer at AbbVie (NYSE: ABBV); and chief technology officer David Morrissey, who once ran an RNAi research group at Novartis.

Intellia will now compete with Editas and CRISPR Therapeutics, all of whom are building on top of different patent portfolios. All three will be pushing forward as other companies with gene therapy, genome editing, and cell therapy technologies also develop programs.

Years after the first wave of gene therapy efforts crashed under the weight of patient deaths in clinical studies, the Dutch firm UniQure (NASDAQ: QURE) kicked off Gene Therapy 2.0 with the field’s first-ever approval: alipogene tiparvovec (Glybera), which the European Union greenlighted in 2012 for the rare disease lipoprotein lipase deficiency.

If Gene Therapy 2.0 is indeed a race, CRISPR/Cas9 companies have to prove their mettle not just against each other but also against other genome-editing technologies. For example, Sangamo Biosciences (NASDAQ: SGMO) has made clinical progress with its so-called zinc finger proteins, with high-profile work in HIV now in Phase 2 and a big development deal with Biogen Idec.

CRISPR/Cas9 is far from ready for therapeutic prime time. (Although a group of Harvard Medical School researchers this month published work that described the use of CRISPR/Cas9 to delete two genes from human hematopoetic stem cells.) The basic idea is that researchers send the Cas9 enzyme into a cell’s nucleus with an RNA guide to seek and snip out a defective gene, and perhaps even replace it with a new, functional strand of code, all by triggering the cell’s natural DNA repair mechanisms.

CRISPR/Cas9 (which stands for “clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease 9”) was first found in bacteria, from which it evolved as a defense system against viruses. Then two researchers—Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of the Helmholtz Centre for Infection Research in Braunschweig, Germany, and the Laboratory for Molecular Infection Medicine at Umeå University, Sweden—made a key modification that suddenly opened up therapeutic possibilities. Their discovery in part was to figure out how to shave the RNA guide down from two nucleic acid strands to one. It was published only two years ago.

In an interesting twist, Doudna is a co-founder of Caribou Biosciences, which spun out of UC Berkeley to commercialize her lab’s work. Caribou has made Intellia its exclusive licensee for all human therapeutic applications. But Doudna herself has no ties to Intellia, according to Caribou CEO Rachel Haurwitz and Intellia CEO Bermingham. Instead, Doudna is a scientific co-founder of Editas—even though Caribou, not Editas, has claim to her foundational work. (Charpentier, meanwhile, has assigned her rights to the foundational work to CRISPR Therapeutics.)

In an interview, CEO Bermingham says the near-term opportunities are in blood-based disorders such as hemophilia and certain cancers. “There are ex vivo applications”—in which the cells are drawn from blood and manipulated outside the patient’s body, then re-infused—“we can address with the technology as it stands today.”

Bermingham declined to give a timeline for getting a therapy into the clinic, but one application he mentioned was chimeric antigen receptor T-cell therapy, or CAR-T, which in early clinical studies has had notable results stopping people’s blood-borne cancer in its tracks. (And one of its purveyors, Juno Therapeutics, just filed to go public less than a year after its emergence from stealth.)

CAR-T is already a gene-modification technology: T cells are removed, genetically engineered to seek out tumor cells with a specific protein on their surface, and put back into the patient. But CAR-T also generates a powerful immune response that can overwhelm a patient with inflammation, an effect that a more precise gene-editing approach–which CRISPR/Cas9 might be—might ameliorate.

Bermingham cautioned that, as with any new technology with grand expectations, it’s important for a small company to choose wisely. “You want to ensure you’re using the system for right therapeutic application,” he says. “There are examples historically of a drug developed using a new platform, but then small molecules”—in other words, the older, cheaper, better understood standby—“came along to make the new product nonviable.”

There are several decisions to make. As with RNAi, delivery into various cell types could be a problem and require a raft of experiments and questions. For example: Should the CRISPR/Cas9 complex—a large enzyme (that’s the Cas9) attached to a nucleic acid strand—be full-sized before it goes into the cell, or should it be encoded, jammed into a viral vector (a well known delivery method in gene therapy), and only expressed once it’s in the cell?

Fortunately for Intellia and its rivals, years of efforts to deliver gene therapy, RNA-mediated drugs, and the like have built a library of data “that we can co-opt,” says Bermingham. “We can’t say what will work right now, but we know how to test it. We’re not starting from zero.”

There’s also a peculiarity of CRISPR/Cas9: so far, the system everyone uses is borrowed from the bacterium S. pyogenes. And it works fine as long as the gene you want to edit is near a specific sequence of the A-C-T-G amino acids that comprise DNA. (The S. pyogenes Cas9 happens to like “GG,” which is good, because there’s a lot of GG sprinkled around the genome.) But inevitably there will be genes to modify or delete nowhere near a “GG,” which means researchers will need a Cas9 from a different bacterium.

Caribou is building a library of Cas9 variations, testing delivery technologies, and a lot more. It has an equity stake in Intellia, and Intellia will have access to its entire platform. “We co-founded Intellia together,” Haurwitz says. “It’s a joint mission and based on a heavy assumption that Intellia can be successful because of [its] privileged relationship with Caribou.”

Haurwitz and Caribou chief scientific officer Andy May are on the Intellia board of directors, joining Bermingham, Atlas partner Jean-Francois Formela, and Leonard.

The scientific founders are Rodolphe Barrangou of North Carolina State University, Erik Sontheimer of the University of Massachusetts Medical School, and Luciano Marraffini of Rockefeller University.

The Novartis investment comes from its research group, the Novartis Institutes for Biomedical Research (NIBR), not from its venture group. NIBR is headquartered in Cambridge. There is no technology agreement between Novartis and Intellia, Bermingham says.

 

Alex Lash is Xconomy's National Biotech Editor. He is based in San Francisco. Follow @alexlash

Trending on Xconomy